Gene expression is regulated at both the transcriptional and post-transcriptional levels. Completion of the human genome project and comparison with ESTs tags have revealed that more than half of the human genes express multiple mRNA isoforms. which has the potential to dramatically enlarge the transcriptome expressed from the genome. thus contributing to the functional diversity in development and disease. Although the pathway for pre-mRNA splicing has been elucidated, little is known about how alternative splicing is regulated in cell physiology. It was recently reported that activated Akt, a well-known oncogene and a key kinase downstream of the PI3K pathway, regulates alternative splicing of the fibronectin gene and that overexpressed SRPK1, antagonizes the effect of activated Akt on fibronectin splicing. I am particularly interested in understanding how alternative splicing is regulated in response to signaling. I will take advantage of knockout mouse systems and a robust splicing array system developed in the Fu lab to (1) investigate the mechanisms of Akt and SRPK1-mediated regulation of alternative splicing, and (2) determine the role of SRPK1 in signal regulated alternative splicing. [unreadable] [unreadable] [unreadable]